Project 3: Inhibition of radiation-induced phenotype conversion in glioblastoma SUMMARY/ABSTRACT Despite a tremendous effort in basic science, clinical trials, drug development, and technical advances in surgery and radiation oncology, glioblastoma remains incurable and improvements in overall survival have been marginal. While radiotherapy is still one of the most effective treatment options for glioblastoma, it cannot control the disease over time. This led us to conclude that novel combination therapies are desperately needed to improve radiation treatment outcome for patients suffering from this disease. The studies outlined in this proposal are based on a hypothesis that is backed by our extensive preliminary data and rigorous published data in the literature. Specifically, we hypothesize that radiation causes a phenotype conversion of differentiated glioma cells into therapy-resistant glioma-initiating cells (GICs), and that interfering with this process will increase the efficiency of radiotherapy. The three aims of this study will address this aspect of glioma biology using an innovative tool to track GICs and their progeny, while leveraging the unique resources and expertise available in the proposed UCLA SPORE in Brain Cancer. In Aim 1, we will study spontaneous and radiation-induced phenotype conversion in glioblastoma under different microenvironmental conditions, and determine if this process generates tumorigenic GICs in vitro and in vivo. In Aim 2, we will attempt to prevent phenotype conversion of non-tumorigenic cells into GICs using dopamine receptor antagonists. Finally, in Aim 3, we propose a novel clinical trial to test whether quetiapine, a dopamine receptor antagonist, can reduce the number of GICs in patients with recurrent GBM and prolong their survival. If successful, results from these studies could have a wider impact on cancer, as these principles may apply not only to glioblastoma but to many other solid tumors.